Causes of death after spinal cord injury

STUDY DESIGN: Mortality review was undertaken of patients who suffered traumatic spinal cord injury (SCI) between 1955 and 1994 inclusive. OBJECTIVES: The study objective was to provide evidence of reasons for the observed reduction in long-term life expectancy for the SCI population. SETTING: Patients were those who had most, if not all, of their inpatient and outpatient care at Royal North Shore Hospital, Spinal Injuries Unit, Sydney, New South Wales, Australia. METHODS: Data on causes of death for 195 patients fitting the inclusion criteria were analysed by actuarial methods using ICD9CM classifications. RESULTS: The incidence of death in the spinal cord injured, from septicaemia, pneumonia and influenza, diseases of the urinary uystem and suicide, are significantly higher than in the general population. The findings confirm variations in potentially treatable causes of death depending on neurological impairment, attained age and duration since injury. Unlike septicaemia and pneumonia, which have shown a significant reduction since 1980, the death rate for suicide alone has risen. CONCLUSION: This analysis identified complications which affect mortality and morbidity in patients suffering from the effects of SCI.     

Long-term assessment of hind limb motor function and neuronal injury following spinal cord ischemia in rats

Recent evidence suggests that brain injury caused by ischemia is a dynamic process characterized by ongoing neuronal loss for at least 14 days after ischemia. However, long-term outcome following spinal cord ischemia has not been extensively examined. Therefore, we investigated the changes of hind limb motor function and neuronal injury during a 14-day recovery period after spinal cord ischemia. Male Sprague-Dawley rats received spinal cord ischemia (n = 64) or sham operation (n = 21). Spinal cord ischemia was induced by inflation of a 2F Fogarty catheter placed into the thoracic aorta for 6, 8, or 10 minutes. The rats were killed 2, 7, or 14 days after reperfusion. Hind limb motor function was assessed with the 21-point Basso, Beattie, and Bresnahan (BBB) scale during the recovery period. The number of normal and necrotic neurons was counted in spinal cord sections stained with hematoxylin/eosin. Longer duration of spinal cord ischemia produced severer hind limb motor dysfunction at each time point. However, BBB scores gradually improved during the 14-day recovery period. Neurologic deterioration was not observed between 7 and 14 days after reperfusion. The number of necrotic neurons peaked 2 days after reperfusion and then decreased. A small number of necrotic neurons were still observed 7 and 14 days after reperfusion in some of the animals. These results indicate that, although hind limb motor function may gradually recover, neuronal loss can be ongoing for 14 days after spinal cord ischemia.     

脊髓损伤后神经细胞程序性死亡方式的研究进展

正脊髓损伤(spinalcordinjury,SCI)是脊柱外伤中严重的并发症,可导致损伤节段以下严重的功能障碍,是青壮年致残的主要原因之一~([1])。由于其致伤机制复杂,临床尚无有效干预手段。近年来的研究表明,神经细胞的死亡是SCI复杂的病理进程中的核心环节~([2])。其中,各种程序性细胞死亡(programmed cell death,PCD)方式因其有可调控性而成为神经保护领域的研究热点~([3])。笔者对SCI后神经     

The effects of the delta-opioid agonist SNC80 on hind-limb motor function and neuronal injury after spinal cord ischemia in rats

Recent investigation suggested neuroprotective efficacy of a delta-opioid agonist in the brain. We investigated the effects of intrathecal treatment with a delta-opioid agonist (SNC80) on spinal cord ischemia (SCI) in rats. SCI was induced with an intraaortic balloon catheter. The animals were randomly allocated to one of the following five groups: 1) SNC80 before 9 min of SCI (SNC-9; n = 12), 2) vehicle before 9 min of SCI (V-9; n = 12), 3) SNC80 before 11 min of SCI (SNC-11; n = 10), 4) vehicle before 11 min of SCI (V-11; n = 12), or 5) sham (n = 12). SNC80 (400 nmol) or vehicle was administered 15 min before SCI. Forty-eight hours after reperfusion, hind-limb motor function was assessed by using the Basso, Beattie, Bresnahan (BBB) scale (0 = paraplegia; 21 = normal) and histological assessment of the L4 and L5 spinal segments was performed. BBB scores in the SNC-9 group were higher compared with those in the V-9 group (P < 0.05), whereas there were no differences in BBB scores between the SNC-11 and V-11 groups. There were significantly more normal neurons in the SNC-9 and SNC-11 groups than in the V-9 and V-11 groups (P < 0.05). The results indicate that intrathecal treatment with the delta-opioid agonist SNC80 can attenuate hind-limb motor dysfunction and neuronal injury after SCI in rats.     

Effect of nerve growth factor on neuronal apoptosis after spinal cord injury in rats

OBJECTIVE: To explore the molecular mechanism of the protective effect of nerve growth factor (NGF) on injured spinal cord. METHODS: The posterior T(8) (the 8th thoracic segment) spinal cords of 60 Wistar rats were injured by impacts caused by objects (weighing 10 g) falling from a height of 2.5 cm with Allen's way. Solution with nerve growth factors (NGF) was given to 30 rats (the NGF group) through a microtubule inserted into the subarachnoid cavity immediately, and at 2, 4, 8, 12 and 24 hours after spinal cord injury (SCI) respectively. Normal saline (NS) with same volume was given to the other 30 rats (the NS group) with the same method. And 5 normal rats were taken as the normal controls. The expression of bcl-2 and bax proteins in spinal cord was detected with immunohistochemistry. The apoptotic neurons in spinal cord were measured with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling of DNA fragments (TUNEL) staining. RESULTS: The positive expression of bcl-2 protein was strong in the normal controls, but decreased in the NS group, and increased significantly in the NGF group as compared with that of the NS group (P<0.01). The positive expression of bax protein was also strong in the normal controls, but increased in the NS group, and decreased significantly in the NGF group as compared with that of the NS group (P<0.01). Apoptotic neurons were found in the NS group, and they decreased significantly in the NGF group as compared with that of the NS group (P<0.01). CONCLUSIONS: NGF can protect the injured nerve tissues through stimulating the expression of bcl-2 protein, inhibiting the expression of bax protein and inhibiting the neuronal apoptosis after SCI.     

神经生长因子对大鼠脊髓损伤后神经元凋亡的影响

目的探讨神经生长因子(NGF)对脊髓损伤保护作用的分子机制.方法采用Allen's法以25 gcm力致伤大鼠T8脊髓,经蛛网膜下腔导管于术后即刻、2、4、8、12、24 h各注入NGF溶液,并与生理盐水组(NS组)和正常对照组作对照,采用免疫组织化学方法和末端单位标记法(TUNEL)原位末端标记法分别检测bcl-2、bax蛋白在脊髓神经元的表达及神经元凋亡情况.结果正常组中脊髓灰质bax蛋白阳性细胞吸光度(A)值为34.51±4.47,NS组中bax蛋白表达增加,以2 h及12 h最为显著,而NGF组与NS组相比,bax蛋白表达明显减少(P＜0.01).正常组中脊髓灰质bcl-2蛋白表达的A值为19.72±2.92,NS组中bcl-2表达下降,而NGF组与NS组相比较,bcl-2蛋白表达明显增多(P＜0.01).TUNEL检测结果显示,正常对照组中未见神经元凋亡,NS组中自2 h后可见神经元凋亡,NGF组与NS组相比,神经元凋亡指数明显减少(P＜0.01).结论NGF能通过抑制bax蛋白的表达,促进bcl-2表达抑制脊髓损伤后神经元凋亡,从而保护损伤的脊髓组织,这可能是NGF对脊髓损伤具有保护作用的机制之一.     

Anti-apoptotic effect of insulin in the control of cell death and neurologic deficit after acute spinal cord injury in rats

Recent studies confirmed that the new cell survival signal pathway of Insulin-PI3K-Akt exerted cyto-protective actions involving anti-apoptosis. This study was undertaken to investigate the potential neuroprotective effects of insulin in the pathogenesis of spinal cord injury (SCI) and evaluate its therapeutic effects in adult rats. SCI was produced by extradural compression using modified Allen's stall with damage energy of 40 g-cm force. One group of rats was subjected to SCI in combination with the administration of recombinant human insulin dissolved in 50% glucose solution at the dose of 1 IU/kg day, for 7 days. At the same time, another group of rats was subjected to SCI in combination with the administration of an equal volume of sterile saline solution. Functional recovery was evaluated using open-field walking, inclined plane tests, and motor evoked potentials (MEPs) during the first 14 days post-trauma. Levels of protein for B-cell lymphoma/leukemia-2 gene (Bcl-2), Caspase-3, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified in the injured spinal cord by Western blot analysis. Neuronal apoptosis was detected by TUNEL, and spinal cord blood flow (SCBF) was measured by laser-Doppler flowmetry (LDF). Ultimately, the data established the effectiveness of insulin treatment in improving neurologic recovery, increasing the expression of anti-apoptotic bcl-2 proteins, inhibiting caspase-3 expression decreasing neuronal apoptosis, reducing the expression of proinflammatory cytokines iNOS and COX-2, and ameliorating microcirculation of injured spinal cord after moderate contusive SCI in rats. In sum, this study reported the beneficial effects of insulin in the treatment of SCI, with the suggestion that insulin should be considered as a potential therapeutic agent.     

Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in Niemann Pick type C1 mice

Niemann Pick disease type C1 (NPC) is an autosomal recessive disease characterized by progressive neurological deterioration leading to premature death. In this study, we hypothesized that human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) have the multifunctional abilities to ameliorate NPC symptoms in the brain. To test this hypothesis, hUCB-MSCs were transplanted into the hippocampus of NPC mice in the early asymptomatic stage. This transplantation resulted in the recovery of motor function in the Rota Rod test and impaired cholesterol homeostasis leading to increased levels of cholesterol efflux-related genes such as LXRα, ABCA1, and ABCG5 while decreased levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase were observed in NPC mice. In the cerebrum, hUCB-MSCs enhanced neuronal cell survival and proliferation, where they directly differentiated into electrically active MAP2-positive neurons as demonstrated by whole-cell patch clamping. In addition, we observed that hUCB-MSCs reduced Purkinje neuronal loss by suppression of inflammatory and apoptotic signaling in the cerebellum as shown by immunohistochemistry. We further investigated how hUCB-MSCs enhance cellular survival and inhibit apoptosis in NPC mice. Neuronal cell survival was associated with increased PI3K/AKT and JAK2/STAT3 signaling; moreover, hUCB-MSCs modulated the levels of GABA/glutamate transporters such as GAT1, EAAT2, EAAT3, and GAD6 in NPC mice as assessed by Western blot analysis. Taken together, our findings suggest that hUCB-MSCs might play multifunctional roles in neuronal cell survival and ameliorating motor deficits of NPC mice.     

Effects of nerve growth factor on neuronal nitric oxide production after spinal cord injury in rats

OBJECTIVE: To explore the protective effects of nerve growth factor (NGF) on injured spinal cord. METHODS: The spinal cord injury (SCI) model of Wistar rats was established by a 10 gx2.5 cm impact force on the T(8) spinal cord. NGF (60 microg/20 microl) was given to the rats of the treatment group immediately and at 2, 4, 8, 12, 24 hours after SCI. The level of neuronal constitutive nitric oxide synthase (ncNOS) and the expression of ncNOS mRNA in the spinal cord were detected by the immunohistochemistry assay and in situ hybridization method. RESULTS: Abnormal expression of ncNOS was detected in the spinal ventral horn motorneuron in injured rats. The levels of ncNOS protein in the NGF group were significantly lower than those in the normal saline group (P<0.05 ). The ncNOS mRNA expression was found in the spinal ventral horn motorneuron in injured rats and the expression in the NGF group was significantly decreased compared with that in the normal saline group (P<0.01). CONCLUSIONS: NGF can protect the injured tissue of the spinal cord by prohibiting abnormal expression of nitric oxide synthase and the neurotoxicity of nitric oxide.     

Minocycline reduces cell death and improves functional recovery after traumatic spinal cord injury in the rat

We examined the effects of minocycline, an anti-inflammatory drug, on functional recovery following spinal cord injury (SCI). Rats received a mild, weight-drop contusion injury to the spinal cord and were treated with the vehicle or minocycline at a dose of 90 mg/kg immediately after SCI and then twice at a dose of 45 mg/kg every 12 h. Injecting minocycline after SCI improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Twenty four to 38 days after SCI, BBB scores were significantly higher in minocycline-treated rats as compared with those in vehicle-treated rats. Morphological analysis showed that lesion size increased progressively in both vehicle-treated and minocycline-treated spinal cords. However, in response to treatment with minocycline, the lesion size was significantly reduced at 21-38 days after SCI when compared to the vehicle control. Minocycline treatment significantly reduced the number of terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive cells 24 h after SCI as compared to that of the vehicle control. DNA gel electrophoresis also revealed a marked decrease in DNA laddering in response to treatment with minocycline. In addition, minocycline treatment significantly reduced the specific caspase-3 activity after SCI as compared to that of vehicle control. Furthermore, RT-PCR analyses revealed that minocycline treatment increased expression of interleukin-10 mRNA but decreased tumor necrosis factor-alpha expression. These data suggest that, after SCI, minocycline treatment modulated expression of cytokines, attenuated cell death and the size of lesions, and improved functional recovery in the injured rat. This approach may provide a therapeutic intervention enabling us to reduce cell death and improve functional recovery after SCI.     

颈椎脊髓损伤早期死亡原因分析

目的探讨颈椎脊髓损伤早期死亡原因。方法回顾性分析1993年1月～2005年12月63例颈椎脊髓损伤早期死亡病例的一般状况、受伤原因、受伤至入院时间、脊柱损伤节段、脊髓损伤严重程度、合并伤、颈椎脊髓损伤影像学表现、治疗方法、过程及结果,总结其早期死亡的原因。结果本组49例因呼吸衰竭死亡,8例因多脏器功能衰竭死亡,2例因癫痫发作导致急性呼吸、循环衰竭死亡,2例因多发伤导致肺部感染及感染性休克死亡,2例因上消化道大出血导致出血性休克死亡。结论呼吸衰竭为颈椎脊髓损伤早期死亡的首要原因,其与脊髓损伤节段及损伤程度密切相关。     

Mortality and causes of death after traumatic spinal cord injury in Estonia

Abstract

Study design

Retrospective population-based study with mortality follow-up.

Objective

To study mortality, causes and risk factors for death in Estonian patients with traumatic spinal cord injury (TSCI).

Setting

All Estonian hospitals.

Methods

Medical records of patients with TSCI from all regional, central, general, and rehabilitation hospitals in Estonia from 1997 to 2007, were retrospectively reviewed. Mortality status was ascertained as of 31 December 2011. Causes of death were collected from the Estonian Causes of Death Registry. Standardized mortality ratios (SMRs) were calculated for the entire sample and for causes of death. A Cox proportional hazards modeling was used to identify the risk indicators for death.

Results

During the observation period (1997–2011) 162 patients of 595 died. Nearly half of the patients (n = 76) died during the first year after TSCI. The main causes of death were external causes (30%), cardiovascular disease (29%). and suicide (8%). The overall SMR was 2.81 (95% confidence interval 2.40–3.28) and SMR was higher for women than for men (3.80 vs. 2.70). Cause-specific SMRs were markedly elevated for sepsis and suicide. Mortality was significantly affected by the age at the time of injury, neurological level, and extent of the injury as well as the year of TSCI and complications.

Conclusion

Life expectancy is significantly decreased in patients with TSCI in Estonia compared with the general population. Deaths during the first year after the injury have an important impact on statistics. Treatment of cardiovascular diseases, infections, and prevention of suicide are useful for reducing mortality in patients with TSCI.     

硫酸软骨素酶ABC促进大鼠脊髓损伤后神经功能恢复的实验研究

目的 探讨硫酸软骨素酶ABC(ChABC)对神经脊髓损伤后运动功能恢复的影响.方法 SD大鼠72只,雌雄不限,随机分为假手术组、生理盐水对照组和ChABC治疗组,采用Allen法打击大鼠胸10脊髓损伤模型,分别在伤后即刻和随后每天一次连续一周蛛网膜下注射生理盐水和ChABC.HE染色和尼氏染色观察各时间点脊髓损伤组织形态和尼氏体及神经元的变化,采用BBB功能评分和运动诱发电位(MEP)观察大鼠的运动功能恢复情况.结果 大鼠脊髓损伤后1周时BBB评分和对照组无显著差别,在2、4周,治疗组评分结果明显优于对照组(P＜0.05;P＜0.01);MEP在1、4周的N1波潜伏期与对照组差异显著(P＜0.05;P＜0.01).HE和Nissl染色显示治疗组的形态和神经元数量要优于对照组.结论 ChABC能促进大鼠脊髓损伤后神经运动功能恢复,并对脊髓组织损伤具有保护作用.     

大鼠脊髓急性损伤后神经细胞凋亡及相关基因表达△

目的研究脊髓急性损伤后神经细胞的凋亡及相关基因的表达.方法大鼠脊髓(T8、T9)经中度压迫损伤后,分别在30min、2h、4h、8h、24h、48h、72h、7d、14d和21d处死取材(各时间组n=4).应用HE染色、免疫组化及凋亡细胞原位末端标记法对脊髓组织进行标记.结果损伤4h后,在损伤段及邻近段可见末端标记阳性神经元,损伤段灰质中阳性细胞数8h达高峰,24h白质中阳性胶质细胞数量达高峰.相邻节段阳性细胞数72h达高峰.损伤后P53及Bax大量表达,而Bcl-2仅少量表达.结论脊髓损伤后神经细胞的凋亡是继发损伤期的重要病理变化.     

大鼠脊髓损伤后血脊髓屏障通透性变化的观察

目的：探讨脊髓损伤后血脊髓屏障通透性变化的机理。方法：采用美国纽约大学（New York University,NYU)脊髓损伤模型,选用体重300－350克雄性成年Wistar大鼠35只,随机分为对照组5只;脊髓损伤组30只,分为伤后4、6、12、24、48、72h6组,每组5只,应用NYU脊髓损伤模型,采用免疫组织化学方法,观察脊髓损伤后不同时间免疫球蛋白G（immunglobularprotein,G,IgG)、补体3的C片断（c fragment of complement3,C3c)的表达变化。结果：脊髓损伤后C3c、IgG渗入了脊髓损伤区域、损伤区域周边及血管,脊髓损伤不同时间段这些区域的免疫标记不同。结论：脊髓损伤后C3c、IgG参与了血脊髓屏障的破坏,参与了脊髓损伤后神经细胞的继发性损伤。     

Hyponatremia-induced transient visual disturbances in acute spinal cord injury

STUDY DESIGN: Case report and literature review. OBJECTIVE: To report an unusual case of prolonged hyponatremia in acute cervical spinal cord injury complicated by visual disturbances and to review the literature regarding the issue. SETTINGS: Spinal Cord Injury Unit in G?teborg, Sweden. METHODS: Retrospective analysis of clinical charts of an individual with traumatic spinal cord injury. RESULTS: A previously healthy 28-year-old man sustained a C7 injury in a motor vehicle accident. His injury was managed surgically and he was overhydrated during the acute management and postoperatively. When weaned off the respirator he was confused and anxious and showed a S-Na of 127 mmol/1 and complained of visual disturbances. The hyponatremia was treated by extra sodium and fluid restriction but fell to a lowest value of 121 mmol/l (Day 14 post injury). Visual acuity was 0.2 on right eye and 0.06 on left eye and the eye examination revealed signs of fundus hypertonicus. CT scans and MRI revealed no signs of brain edema. The patient was further treated by mineral corticoids and fluid restriction for 4 months and his vision improved slightly, but on a final examination 125 days post injury he was found to have an afferent pupillary defect on his left eye, and bilateral atrophy of the visual nerves. The hyponatremia resolved and 6 months post injury he showed a normal S-Na. CONCLUSIONS: SCI individuals are at increased risk of developing hyponatremia. The reported complication of visual disturbances further stresses the importance of prevention of overhydration and of timely management of hyponatremia in this group of patients.